The present invention relates to a process for preparing 3,4-dehydroprolines and 3,4-dehydropiperidines. In particular, the invention relates to a process for preparing compounds of the formula I 
in which
R is hydrogen, C1-C6-alkoxy, xe2x80x94NHC1-C6-alkyl, N(C1-C6-alkyl)2, OH, NH2 
R1 is hydrogen, C1-C6-alkyl, Me3Si, C1-C6-alkyl-S
R2 is Boc, C1-C6-acyl, mesyl, benzenesulfonyl, tosyl, trifluoroacetyl, A1-A3-peptide
n is 1, 2
R4 is H, C1-C6-alkyl.
3,4-Dehydroprolines are prepared starting from 4-hydroxyproline via the Tschugaeff reaction (P. Grogg, Angew. Chem. 92 (1980) 761). In addition to relatively poor yields (64%), this method requires highly toxic compounds to be handled, such as carbon disulfide, methyl iodide and methyl mercaptan. The pyrolytic decomposition at from 180 to 190xc2x0 C. and 12 Torr requires more complex technology.
Instead of the xanthogenates, it is also possible to react corresponding iodides, sulfoxides or selenium oxides by thermolysis (J.-R. Dormoy, Synthesis (1982) 752). However, this does not solve the fundamental problems regarding toxicity and technical expense.
Achiral syntheses usually use pyrrolecarboxylic acid as starting material, which is reduced using phosphonium iodide/hydrogen iodide (J. W. Scott, Synth. Commun. 10 (1980) 529). The racemate is then separated by crystallization using chiral amines (S. S. Kerwar, J. Bio. Chem. 251 (1976) 503; U.S. Pat. No. 4,066,658) or tartaric acid (A. Corbella, Chem. Ind. (1969) 583). This synthesis has the disadvantages that highly toxic phosphane has to be handled, and that the maximum yield for the resolution of the racemate is 50%.
WO 98/04523 describes the elimination of sulfonic esters of hydroxyproline ester and subsequent enzymatic resolution of the racemate.
Until recently, the Birch reduction of pyrrole derivatives was not known. In J. Org. Chem. 61 (1996) 7664 T. J. Donohoe describes, for the first time, the achiral Birch reduction of pyrrole-2-carboxylic acid derivatives. As described above, up to now it was only possible to separate them into the enantiomers by classical or enzymatic resolution of the racemate.
WO 98/55456 describes the diastereoselective Birch reduction of chiral pyrrole-2-carboxylic esters and pyrrole-2-carboxamides.
The synthesis of 3,4-dehydropiperidine-2-carboxylic acid derivatives is described in D""Ambra, Bell, J. Org. Chem. 54 (1989) 5632, and in Krogsgaard-Larsen, J. Labeled Compd. 19 (1982) 689. Both syntheses require extremely toxic chemicals (isocyanates, nitrosamines) to be handled and afford the desired product only in poor yields.
It is an object of the present invention to prepare 3,4-dehydroprolines and 3,4-dehydropiperidines of the formula I using a simple reaction sequence.
The preparation of 3-pyrroline, for example via metathesis, is comprehensively documented in the more recent literature (Grubbs, J. Org. Chem. 62 (1997) 7310; Pandit, Tetrahedron Lett. 37 (1996) 547; Grubbs, J. Am. Chem. Soc. 115 (1993) 9856; Moreno-Manas, Tetrahedron 54 (1998) 14869).
Alkylations of 3-pyrroline in the 2 position, for example Meyers, J. Am. Chem. Soc. 107 (1985) 7974; Macdonald, J. Org. Chem. 45 (1980) 193; Francke, Liebigs Ann. (1995) 193, and the hydroformylation which affords derivatives of proline (Izawa, Bull. Chem. Soc. Jpn. 64 (1991) 620) are known.
Carboxylations of pyrrolidine are known very well, for example Beak, J. Am. Chem. Soc. 116 (1994) 3231. However, Colegate, Austral. J. Chem. 37 (1984) 1503 teaches that, in an analogous deprotonation of methoxycarbonyl-3-pyrroline, this compound undergoes an undesirable intermolecular reaction, giving N-methoxycarbonyl-3-pyrroline-2-carboxylic acid 1-(3-pyrrolinide) in a yield of 65%.
Surprisingly, it has been found that pyrrolines and 3,4-dehydropiperidines of the formula II 
in which
R2 is Boc, C1-C6-acyl, mesyl, benzenesulfonyl, tosyl, trifluoroacetyl, A1-A3-peptide
R4 is H, C1-C6-alkyl
n is 1 or 2
can be reacted in the presence of a carboxylating agent or carbonylating agent of the formula III 
in which
R is hydrogen, C1-C6-alkoxy, xe2x80x94NHC1-C6-alkyl, xe2x80x94N(C1-C6-alkyl)2, OH, NH2 
Y is Cl, C1-C6-alkoxy, xe2x80x94NHC1-C6-alkyl, xe2x80x94N(C1-C6-alkyl)2, N(C1-C6-alkyl)OC1-C6, where R is not OH,
or, for R=OH in formula I, with CO2, together with a strong base, preferably an alkali metal amide, and, if appropriate, hydrolyzed or reacted with an agent of the formula IV
R3xe2x80x94Xxe2x80x83xe2x80x83(IV)
in which
X is Cl, Br, I, MesO, TosO, triflate
R3 is hydrogen, C1-C6-alkyl, Me3Si, C1-C6-alkyl-S or NH4 or
R3xe2x80x94X is (C1-C6-alkyl-S)2 
to give the desired dehydroprolines and dehydropiperidines in good yields.
Preferred alkali metal amides are lithium amides and sodium amides of the formula V
MNR5R6xe2x80x83xe2x80x83(V)
where
M is Na, Li,
R5 is H, C1-C6-alkyl
R6 is H, C1-C6-alkyl.
The preferred meaning of the formula III is di-C1-C6-alkyl carbonate, in particular dimethyl carbonate and diethyl carbonate.
A1-A3-peptide is to be understood as meaning a radical comprising up to three amino acids, the amino acids being natural (proteinogenic) and unnatural (nonproteinogenic) amino acids. The A1-A3 peptide can be derivatized or protected by customary protective groups. A1-A3-peptide includes partially or fully peptidomimetic structures.
A1, A2 and A3 are to be understood as meaning, in particular, the following amino acids: t-butylglycine, t-butylalanine, adamantylglycine, adamantylalanine, natural amino acids, their D-enantiomers, cyclopropylglycine, cycloheptylglycine, cycloheptylalanine, cyclobutylglycine, cyclopentylglycine, cyclohexylglycine, cyclopropylalanine, cyclobutylalanine, cyclopentylalanine, cyclohexylalanine, all isomers of furanylglycine, furanylalanine, naphthylglycine, naphthylalanine, thiophenylglycine, thiophenylalanine, isoquinolineglycine, isoquinolinealanine, quinolineglycine, quinolinealanine, pyrrolylglycine, pyrrolylalanine, imidazolylglycine, imidazolylalanine, 3,4-dehydroproline.
The reaction is carried out in solvents which are inert under the reaction conditions. Preferred solvents are C2-C8 hydrocarbons, in particular hexanes, THF and C1-C6-ethers, C1-C6-ether/DMPU mixtures, dioxane and mixtures of the solvents mentioned.
The reaction is generally carried out at from xe2x88x92100 to +100xc2x0 C. and in a pressure range from 1 to 200 bar. Preference is given to a temperature range of from xe2x88x9220 to +20xc2x0 C.
In general, the reaction is terminated in a customary manner when it is no longer possible to detect pyrroline derivatives or dehydropiperidine derivatives in the reaction mixture (for example by GC, HPLC, TLC).
Work-up to give the product of the process is generally carried out by customary methods, such as distillation, filtration, centrifugation or extraction.
The process according to the invention is carried out batchwise, for example in a stirred reactor. However, the fact that the process can be carried out in a simple manner offers the advantage of making it possible to convert it to continuous operation, for example using a reaction tube or a stirred-reactor cascade.
If desired, the resultinq crude products can be purified further, for example by crystallization, extraction or chromatography.
The 3,4-dehydroprolines and 3,4-dehydropiperidines of the formula I which can be prepared in a simple manner by the process according to the invention are useful intermediates for the synthesis of dyes, crop protection agents or drugs, in particular thrombin inhibitors, as described above, for example, in the publications WO 94/29336, WO 95/35309, WO 96/17860, WO 96/24609, WO 96/25426, WO 98/06741.